Intestinal activating transcription factor 4 regulates stress-related behavioral alterations via paraventricular thalamus in male mice.

Chronic stress induces depression- and anxiety-related behaviors, which are common mental disorders accompanied not only by dysfunction of the brain but also of the intestine. Activating transcription factor 4 (ATF4) is a stress-induced gene, and we previously show that it is important for gut functions; however, the contribution of the intestinal ATF4 to stress-related behaviors is not known. Here, we show that chronic stress inhibits the expression of ATF4 in gut epithelial cells. ATF4 overexpression in the colon relieves stress-related behavioral alterations in male mice, as measured by open-field test, elevated plus-maze test, and tail suspension test, whereas intestine-specific ATF4 knockout induces stress-related behavioral alterations in male mice. Furthermore, glutamatergic neurons are inhibited in the paraventricular thalamus (PVT) of two strains of intestinal ATF4-deficient mice, and selective activation of these neurons alleviates stress-related behavioral alterations in intestinal ATF4-deficient mice. The highly expressed gut-secreted peptide trefoil factor 3 (TFF3) is chosen from RNA-Seq data from ATF4 deletion mice and demonstrated decreased in gut epithelial cells, which is directly regulated by ATF4. Injection of TFF3 reverses stress-related behaviors in ATF4 knockout mice, and the beneficial effects of TFF3 are blocked by inhibiting PVT glutamatergic neurons using DREADDs. In summary, this study demonstrates the function of ATF4 in the gut-brain regulation of stress-related behavioral alterations, via TFF3 modulating PVT neural activity. This research provides evidence of gut signals regulating stress-related behavioral alterations and identifies possible drug targets for the treatment of stress-related behavioral disorders.

A study on the mechanism of Beclin-1 m6A modification mediated by catalpol in protection against neuronal injury and autophagy following cerebral ischemia.

OBJECTIVE: Catalpol (CAT) has various pharmacological activities and plays a protective role in cerebral ischemia. It has been reported that CAT played a protective role in cerebral ischemia by upregulaing NRF1 expression. Bioinformatics analysis reveals that NRF1 can be used as a transcription factor to bind to the histone acetyltransferase KAT2A. However, the role of KAT2A in cerebral ischemia remains to be studied. Therefore, we aimed to investigate the role of CAT in cerebral ischemia and its related mechanism. METHODS: In vitro, a cell model of oxygen and glucose deprivation/reperfusion (OGD/R) was constructed, followed by evaluation of neuronal injury and the expression of METTL3, Beclin-1, NRF1, and KAT2A. In vivo, a MCAO rat model was prepared by means of focal cerebral ischemia, followed by assessment of neurological deficit and brain injury in MCAO rats. Neuronal autophagy was evaluated by observation of autophagosomes in neurons or brain tissues by TEM and detection of the expression of LC3 and p62. RESULTS: In vivo, CAT reduced the neurological function deficit and infarct volume, inhibited neuronal apoptosis in the cerebral cortex, and significantly improved neuronal injury and excessive autophagy in MCAO rats. In vitro, CAT restored OGD/R-inhibited cell viability, inhibited cell apoptosis, LDH release, and neuronal autophagy. Mechanistically, CAT upregulated NRF1, NRF1 activated METTL3 via KAT2A transcription, and METTL3 inhibited Beclin-1 via m6A modification. CONCLUSION: CAT activated the NRF1/KAT2A/METTL3 axis and downregulated Beclin-1 expression, thus relieving neuronal injury and excessive autophagy after cerebral ischemia.

Magnetic Microbead-Based Herringbone Chip for Sensitive Detection of Human Immunodeficiency Virus.

The microfluidic chip-based nucleic acid detection method significantly improves the sensitivity since it precisely controls the microfluidic flow in microchannels. Nonetheless, significant challenges still exist in improving the detection efficiency to meet the demand for rapid detection of trace substances. This work provides a novel magnetic herringbone (M-HB) structure in a microfluidic chip, and its advantage in rapid and sensitive detection is verified by taking complementary DNA (cDNA) sequences of human immunodeficiency virus (HIV) detection as an example. The M-HB structure is designed based on controlling the magnetic field distribution in the micrometer scale and is formed by accumulation of magnetic microbeads (MMBs). Hence, M-HB is similar to a nanopore microstructure, which has a higher contact area and probe density. All of the above is conducive to improving sensitivity in microfluidic chips. The M-HB chip is stable and easy to form, which can linearly detect cDNA sequences of HIV quantitatively ranging from 1 to 20 nM with a detection limit of 0.073 nM. Compared to the traditional herringbone structure, this structure is easier to form and release by controlling the magnetic field, which is flexible and helps in further study. Results show that this chip can sensitively detect the cDNA sequences of HIV in blood samples, demonstrating that it is a powerful platform to rapidly and sensitively detect multiple nucleic acid-related viruses of infectious diseases.

Intravoxel Incoherent Motion Diffusion-Weighted MR Imaging and Venous Tumor Thrombus Consistency in Renal Cell Carcinoma.

BACKGROUND: Venous tumor thrombus (VTT) consistency of renal cell carcinoma (RCC) is an important consideration in nephrectomy plus thrombectomy. However, evaluation of VTT consistency through preoperative MR imaging is lacking. PURPOSE: To evaluate VTT consistency of RCC through intravoxel incoherent motion-diffusion weighted imaging (IVIM-DWI) derived parameters (Dt , Dp , f, and ADC) and the apparent diffusion coefficient (ADC) value. STUDY TYPE: Retrospective. POPULATION: One hundred and nineteen patients (aged 55.8 ± 11.5 years, 85 male) with histologically-proven RCC and VTT who underwent radical resection. FIELD STRENGTH/SEQUENCES: 3.0-T; two-dimensional single-shot diffusion-weighted echo planar imaging sequence at 9 b-values (0-800 s/mm2 ). ASSESSMENT: IVIM parameters and ADC values of the primary tumor and the VTT were calculated. The VTT consistency (friable vs. solid) was determined through intraoperative findings of two urologists. The accuracy of VTT consistency classification based on the individual IVIM parameters of primary tumors and of VTT, and based on models combining parameters, was assessed. Type of operation, intra-operative blood loss, and operation length were recorded. STATISTICAL TESTS: Shapiro-Wilk test; Mann-Whitney U test; Student's t-test; Chi-square test; Receiver operating characteristic (ROC) analysis. Statistical significance level was P < 0.05. RESULTS: Of the enrolled 119 patients, 33 patients (27.7%) had friable VTT. Patients with friable VTT were significantly more likely to experience open surgery, have significantly more intraoperative blood loss, and significantly longer operative duration. The area under the ROC curve (AUC) values of Dt of the primary tumor and VTT in classifying VTT consistency were 0.758 (95% CI 0.671-0.832) and 0.712 (95% CI 0.622-0.792), respectively. The AUC value of the model combining Dp and Dt of VTT was 0.800 (95% CI 0.717-0.868). Furthermore, the AUC of the model combining Dp and Dt of VTT and Dt of the primary tumor was 0.886 (95% CI 0.814-0.937). CONCLUSION: IVIM-derived parameters had the potential to predict VTT consistency of RCC. EVIDENCE LEVEL: 3 Technical Efficacy: Stage 2.

An Improved Nested U-Net Network for Fluorescence In Situ Hybridization Cell Image Segmentation.

Fluorescence in situ hybridization (FISH) is a powerful cytogenetic method used to precisely detect and localize nucleic acid sequences. This technique is proving to be an invaluable tool in medical diagnostics and has made significant contributions to biology and the life sciences. However, the number of cells is large and the nucleic acid sequences are disorganized in the FISH images taken using the microscope. Processing and analyzing images is a time-consuming and laborious task for researchers, as it can easily tire the human eyes and lead to errors in judgment. In recent years, deep learning has made significant progress in the field of medical imaging, especially the successful application of introducing the attention mechanism. The attention mechanism, as a key component of deep learning, improves the understanding and interpretation of medical images by giving different weights to different regions of the image, enabling the model to focus more on important features. To address the challenges in FISH image analysis, we combined medical imaging with deep learning to develop the SEAM-Unet++ automated cell contour segmentation algorithm with integrated attention mechanism. The significant advantage of this algorithm is that it improves the accuracy of cell contours in FISH images. Experiments have demonstrated that by introducing the attention mechanism, our method is able to segment cells that are adherent to each other more efficiently.

Real-Time Multi-Sensor Joint Fault Diagnosis Method for Permanent Magnet Traction Drive Systems Based on Structural Analysis.

Sensor faults are one of the most common faults that cause performance degradation or functional loss in permanent magnet traction drive systems (PMTDSs). To quickly diagnose faulty sensors, this paper proposes a real-time joint diagnosis method for multi-sensor faults based on structural analysis. Firstly, based on limited monitoring signals on board, a structured model of the system was established using the structural analysis method. The isolation and detectability of faulty sensors were analyzed using the Dulmage-Mendelsohn decomposition method. Secondly, the minimum collision set method was used to calculate the minimum overdetermined equation set, transforming the higher-order system model into multiple related subsystem models, thereby reducing modeling complexity and facilitating system implementation. Next, residual vectors were constructed based on multiple subsystem models, and fault detection and isolation strategies were designed using the correlation between each subsystem model and the relevant sensors. The validation results of the physical testing platform based on online fault data recordings showed that the proposed method could achieve rapid fault detection and the localization of multi-sensor faults in PMTDS and had a good application value.

BAP1-related signature predicts benefits from immunotherapy over VEGFR/mTOR inhibitors in ccRCC: a retrospective analysis of JAVELIN Renal 101 and checkmate-009/010/025 trials.

BACKGROUND: In patients with advanced clear cell renal cell carcinoma, despite the undoubted benefits from immune checkpoint inhibitor (ICI)-based therapies over monotherapies of angiogenic/mTOR inhibitors in the intention-to-treat population, approximately a quarter of the patients can scarcely gain advantage from ICIs, prompting the search for predictive biomarkers for patient selection. METHODS: Clinical and multi-omic data of 2428 ccRCC patients were obtained from The Cancer Genome Atlas (TCGA, n = 537), JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib, n = 885), and CheckMate-009/010/025 (nivolumab vs. everolimus, n = 1006). RESULTS: BAP1 mutations were associated with large progression-free survival (PFS) benefits from ICI-based immunotherapies over sunitinib/everolimus (pooled estimate of interaction HR = 0.71, 95% CI 0.51-0.99, P = 0.045). Using the top 20 BAP1 mutation-associated differentially expressed genes (DEGs) generated from the TCGA cohort, we developed the BAP1-score, negatively correlated with angiogenesis and positively correlated with multiple immune-related signatures concerning immune cell infiltration, antigen presentation, B/T cell receptor, interleukin, programmed death-1, and interferon. A high BAP1-score indicated remarkable PFS benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors (avelumab plus axitinib vs. sunitinib: HR = 0.55, 95% CI 0.43-0.70, P < 0.001; nivolumab vs. everolimus: HR = 0.72, 95% CI 0.52-1.00, P = 0.045), while these benefits were negligible in the low BAP1-score subgroup (HR = 1.16 and 1.02, respectively). CONCLUSION: In advanced ccRCCs, the BAP1-score is a biologically and clinically significant predictor of immune microenvironment and the clinical benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors, demonstrating its potential utility in optimizing the personalized therapeutic strategies in patients with advanced ccRCC.

Robotic Level IV Inferior Vena Cava Thrombectomy Using an Intrapericardial Control Technique: Is It Safe Without Cardiopulmonary Bypass?

PURPOSE: We introduce an intrapericardial control technique using a robotic approach in the surgical treatment of renal tumor with level IV inferior vena cava thrombus to decrease the severe complications associated with cardiopulmonary bypass and deep hypothermic circulatory arrest. MATERIALS AND METHODS: Eight patients with level IV inferior vena cava thrombi not extending into the atrium underwent transabdominal-transdiaphragmatic robot-assisted inferior vena cava thrombectomy obviating cardiopulmonary bypass/deep hypothermic circulatory arrest (cardiopulmonary bypass-free group) by an expert team comprising urological, hepatobiliary, and cardiovascular surgeons. The central diaphragm tendon and pericardium were transabdominally dissected until the intrapericardial inferior vena cava were exposed and looped proximal to the cranial end of the thrombi under intraoperative ultrasound guidance. As controls, 14 patients who underwent robot-assisted inferior vena cava thrombectomy with cardiopulmonary bypass (cardiopulmonary bypass group) and 25 patients who underwent open thrombectomy with cardiopulmonary bypass/deep hypothermic circulatory arrest (cardiopulmonary bypass/deep hypothermic circulatory arrest group) were included. Clinicopathological, operative, and survival outcomes were retrospectively analyzed. RESULTS: Eight robot-assisted inferior vena cava thrombectomies were successfully performed without cardiopulmonary bypass, with 1 open conversion. The median operation time and first porta hepatis occlusion time were shorter, and estimated blood loss was lower in the cardiopulmonary bypass-free group as compared to the cardiopulmonary bypass group (540 vs 586.5 minutes, 16.5 vs 38.5. minutes, and 2,050 vs 3,500 mL, respectively). Severe complications (level IV-V) were also lower in the cardiopulmonary bypass-free group than in cardiopulmonary bypass and cardiopulmonary bypass/deep hypothermic circulatory arrest groups (25% vs 50% vs 40%). Oncologic outcomes were comparable among the 3 groups in short-term follow-up. CONCLUSIONS: Pure transabdominal-transdiaphragmatic robot-assisted inferior vena cava thrombectomy without cardiopulmonary bypass/deep hypothermic circulatory arrest represents as an alternative minimally invasive approach for selected level IV inferior vena cava thrombi.

Covalent Organic Framework-Supported Metallocene for Ethylene Polymerization.

The loading of homogeneous catalysts with support can dramatically improve their performance in olefin polymerization. However, the challenge lies in the development of supported catalysts with well-defined pore structures and good compatibility to achieve high catalytic activity and product performance. Herein, we report the use of an emergent class of porous material-covalent organic framework material (COF) as a carrier to support metallocene catalyst-Cp2 ZrCl2 for ethylene polymerization. The COF-supported catalyst demonstrates a higher catalytic activity of 31.1×106  g mol-1 h-1 at 140 °C, compared with 11.2×106  g mol-1 h-1 for the homogenous one. The resulting polyethylene (PE) products possess higher weight-average molecular weight (Mw ) and narrower molecular weight distribution (Ð) after COF supporting, that is, Mw increases from 160 to 308 kDa and Ð drops from 3.3 to 2.2. The melting point (Tm ) is also increased by up to 5.2 °C. Moreover, the PE product possesses a characteristic filamentous microstructure and demonstrates an increased tensile strength from 19.0 to 30.7 MPa and elongation at break from 350 to 1400 % after catalyst loading. We believe that the use of COF carriers will facilitate the future development of supported catalysts for highly efficient olefin polymerization and high-performance polyolefins.

A single-centre, open-label, single-arm, fixed-sequence pharmacokinetic study of SHR3680 on repaglinide and bupropion in prostate cancer patients.

To evaluate the pharmacokinetic effects of SHR3680 on repaglinide and bupropion and its metabolite hydroxybupropion. METHODS: A single-centre, open-label, single-arm, fixed-sequence clinical trial in 18 patients with prostate cancer. RESULTS: After a single oral dose of 0.5 mg repaglinide and SHR3680, geometric mean peak plasma concentration (Cmax ) of plasma repaglinide was 14.240 and 5.887 ng/mL, geometric mean area under the concentration-time curve (AUC0-t )was 20.577 and 7.320 h ng/mL, geometric mean AUC0-∞ was 20.949 and 7.451 h ng/mL, mean half-life (t1/2 ) was 1.629 and 1.195 hours, and geometric mean oral clearance (CL/F) was 23.867 and 67.107 L/h, respectively. After a single oral administration of 150 mg bupropion and SHR3680, geometric mean Cmax of plasma bupropion was 85.430 and 33.747 ng/mL, geometric mean AUC0-t was 1003.896 and 380.158 h ng/mL, geometric mean AUC0-∞ was 1038.054 and 401.387 h ng/mL, mean t1/2 was 22.533 and 17.733 hours, and geometric mean CL/F was 144.501 and 373.705 L/h, respectively. The plasma geometric mean Cmax of its main active metabolic hydroxybupropion was 268.113 and 177.318 ng/mL, geometric mean AUC0-t was 14 283.087 and 5420.219 h ng/mL, geometric mean AUC0-∞ was 15 218.158 and 5364.625 h ng/mL, mean t1/2 were 36.069 and 16.688 hours, and geometric mean CL/F was 8.623 L/h and 27.961 L/h, respectively. CONCLUSION: Coadministration of SHR3680 with repaglinide or bupropion significantly shortened the elimination half-lives, significantly increased the apparent clearance rate, and significantly decreased the in vivo exposure of repaglinide, bupropion and hydroxybupropion compared with single administration of repaglinide or bupropion.

Comparison of cardiac magnetic resonance imaging and fluorodeoxyglucose positron emission tomography in the assessment of cardiac sarcoidosis: Meta-analysis and systematic review.

AIM: Fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) and cardiac magnetic resonance (CMR) are frequently used advanced cardiac imaging to diagnose cardiac sarcoidosis (CS). We conducted a meta-analysis and systematic review to compare diagnostic parameters of FDG-PET and CMR in the diagnosis of cardiac sarcoidosis (CS). METHODS: We searched PubMed, EMBASE, and Scopus databases from their inception to 9/30/2021 with search terms "cardiac sarcoidosis" AND "cardiac magnetic resonance imaging" AND "positronemission tomography". We extracted patient characteristics, results of the FDG-PET and CMR, and adverse outcomes from the included studies. Adverse outcomes served as a reference standard for the evaluation of FDG-PET and CMR. RESULTS: We included 4 studies in the meta-analysis which provided adverse outcomes and all patients underwent FDG-PET and CMR. There were 237 patients, 60.3% male, and ages ranged from 50-53 years. There were 45 events in 237 patients from four studies included in the meta-analyses. The pooled sensitivity (95% confidence interval-CI) and specificity (CI) of CMR in predicting an adverse event were 0.94 (0.79-0.98) and 0.49 (0.40-0.59), respectively. The pooled sensitivity (CI) and specificity (CI) of FDG-PET in predicting an adverse event were 0.51 (0.26-0.75) and 0.60 (0.35-0.81), respectively. CONCLUSION: CMR was more sensitive but less specific than FDG-PET in predicting adverse events; however, the study population and definition of a positive test need to be considered while interpreting the results.

Comparison of cardiac magnetic resonance imaging and fluorodeoxyglucose positron emission tomography in the assessment of myocardial viability: meta-analysis and systematic review.

AIM: Contrast-enhanced cardiac magnetic resonance (Ce-CMR) and Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) are frequently utilized in clinical practice to assess myocardial viability. However, studies evaluating direct comparison between Ce-CMR and FDG-PET have a smaller sample size, and no clear distinction between the two imaging modalities has been defined. To address this gap, we conducted a meta-analysis of studies comparing Ce-CMR and FDG-PET for the assessment of myocardial viability. METHODS: We searched PubMed, EMBASE, Scopus, and Web of Science databases from their inception to 4/20/2022 with search terms "viability" AND "heart diseases" AND "cardiac magnetic resonance imaging" AND "positron-emission tomography." We extracted patient characteristics, segment level viability assessment according to Ce-CMR and FDG-PET, and change in regional wall motion abnormalities (RWMA) at follow-up. RESULTS: We included four studies in the meta-analysis which provided viability assessment with Ce-CMR and FDG-PET in all patients and change in RWMA at follow-up. There were 82 patients among the four included studies, and 585 segments were compared for viability assessment. There were 59 (72%) males, and mean age was 65 years. The sensitivity (95% confidence interval-CI) and specificity (CI) of Ce-CMR for predicting myocardial recovery were 0.88 (0.66-0.96) and 0.64 (0.49-0.77), respectively. The sensitivity (CI) and specificity (CI) of FDG-PET for predicting myocardial recovery were 0.91 (0.63-0.99) and 0.67 (0.49-0.81), respectively. CONCLUSION: FDG-PET and Ce-CMR have comparable diagnostic parameters in myocardial viability assessment and are consistent with prior research.

Adrenocortical carcinoma with venous tumor invasion: is there a role for mini-invasive surgery?

OBJECTIVE: This study aims to investigate early oncologic outcomes in patients with adrenocortical carcinoma (ACC) with venous invasion (VI) treated using both open and mini-invasive approaches. PATIENTS AND MATERIALS: We conducted a retrospective analysis of 4 international referral center databases, including all the patients undergoing adrenalectomy for ACC with VI from January 2007 to March 2020. According to CT scan or MRI, the tumor thrombus was classified into four levels: (1) adrenal vein invasion; (2) renal vein invasion; (3) infra-hepatic Inferior vena cava (IVC); and (4) retro-hepatic IVC. In addition, we divided our patients into patients who had undergone open surgery and mini-invasive surgery. RESULTS: We identified 20 patients with a median follow-up of 12 months. The median tumor size was 110mm. ENSAT stage was II in 4 patients, III in 13 patients, and IV in 3 patients. Tumor thrombus extended in the adrenal vein (n=5), renal vein (n=1), infra-hepatic IVC (n=9), or into the retro-hepatic IVC (n=5). Ten patients were treated with a mini-invasive approach. The patient treated with an open approach reported a more aggressive disease. The two groups did not differ in surgical margins, surgical time, blood losses, complications, and length of stay. The prognosis resulted worse in the patient undergoing open. Kaplan-Meier analysis indicated a difference in OS for the patients stratified by ENSAT stage (Log-rank p=0.011); we also reported a difference in DFS for patients stratified for thrombus extension (p=0.004) and ENSAT stage (p<0.001). CONCLUSION: The DFS of patients with VI from ACC is influenced by the staging and the extension of the venous invasion; the staging influences the OS. The mini-invasive approach seems feasible in selected patients; however, further studies investigating the oncological outcomes are needed. A mini-invasive approach for adrenal tumors with venous invasion is an explorable option in very selected patients.

MAC5, an RNA-binding protein, protects pri-miRNAs from SERRATE-dependent exoribonuclease activities.

MAC5 is a component of the conserved MOS4-associated complex. It plays critical roles in development and immunity. Here we report that MAC5 is required for microRNA (miRNA) biogenesis. MAC5 interacts with Serrate (SE), which is a core component of the microprocessor that processes primary miRNA transcripts (pri-miRNAs) into miRNAs and binds the stem-loop region of pri-miRNAs. MAC5 is essential for both the efficient processing and the stability of pri-miRNAs. Interestingly, the reduction of pri-miRNA levels in mac5 is partially caused by XRN2/XRN3, the nuclear-localized 5'-to-3' exoribonucleases, and depends on SE. These results reveal that MAC5 plays a dual role in promoting pri-miRNA processing and stability through its interaction with SE and/or pri-miRNAs. This study also uncovers that pri-miRNAs need to be protected from nuclear RNA decay machinery, which is connected to the microprocessor.

Percutaneous kyphoplasty combined with zoledronic acid for the treatment of primary osteoporotic vertebral compression fracture: a prospective, multicenter study.

INTRODUCTION: To explore the therapeutic efficacy of percutaneous kyphoplasty (PKP) combined with zoledronic acid (ZOL) in postmenopausal women and adult men with osteoporotic vertebral compression fracture (OVCF). MATERIALS AND METHODS: A total of 238 patients with OVCF were randomly assigned to the control or ZOL group: 119 patients were treated with only PKP (control group), and 119 were treated with ZOL infusion after PKP (ZOL group). Clinical, radiological and laboratory indices were evaluated at follow-up. RESULTS: The visual analog scale (VAS) score and Oswestry Disability Index (ODI) were significantly higher in both groups post-treatment than at baseline (all p < 0.01). The bone mineral density (BMD) of the proximal femoral neck and height of the injured vertebra were significantly increased after treatment compared with before treatment, and the Cobb angle of the injured vertebra was significantly decreased in both groups (all p < 0.01). However, the bone metabolism indices (type I procollagen amino-terminal peptide (PINP), beta type I collagen carboxy-terminal peptide (ß-CTX), and osteocalcin in the N-terminal molecular fragment (NMID)) were significantly lower post-treatment than at baseline in only the ZOL group (all p < 0.01). The VAS score, ODI, BMD, PINP level, ß-CTX level, NMID level, vertebral height and Cobb angle of the injured vertebra were significantly higher in the ZOL group than in the control group (all p < 0.01). There were no significant differences in the postoperative bone cement leakage rate between the two groups. At follow-up, new OVCFs were experienced by 16 patients in the control group and 2 patients in the ZOL group (p < 0.01). CONCLUSION: The therapeutic efficacy of PKP combined with ZOL for primary OVCF is clinically beneficial and warrants further study.

LINC00240/miR-155 axis regulates function of trophoblasts and M2 macrophage polarization via modulating oxidative stress-induced pyroptosis in preeclampsia.

BACKGROUND: This study aimed to investigate the effects of LINC00240/miR-155/Nrf2 axis on trophoblast function and macrophage polarization in the pathogenesis of preeclampsia. METHODS: Bindings between LINC00240, miR-155 and Nrf2 were validated by dual luciferase reporter assay or RNA-immunoprecipitation. Cell proliferation, migration, invasion, and pyroptosis were detected by CCK-8, clone formation, wound healing, Transwell system, and flow cytometry, respectively. Macrophage polarization was tested by flow cytometry. The expression levels of LINC00240, miR-155, Nrf2, and oxidative stress and pyroptosis-related markers in in vitro and in vivo preeclampsia models were analyzed by qPCR, western blot, or ELISA assays. Blood pressure, urine protein levels, liver and kidney damages, and trophoblast markers in placenta tissues were further studied in vivo. RESULTS: Placenta tissues from preeclampsia patients and animals showed decreased LINC00240 and Nrf2 and increased miR-155 expression levels, and the decreased M2 macrophage polarization. LINC00240 directly bound and inhibited expression of miR-155, which then inhibited oxidative stress-induced pyroptosis, promoting proliferation, migration and invasion abilities of trophoblasts, and M2 macrophage polarization. Inhibition of miR-155 led to increased Nrf2 expression and similar changes as LINC00240 overexpression in trophoblast function and macrophage polarization. Overexpression of LINC00240 in in vivo preeclampsia model decreased blood pressure, urine protein, liver and kidney damages, increased fetal weight and length, and induced trophoblast function and M2 macrophage polarization. CONCLUSION: LINC00240 inhibited symptoms of preeclampsia through regulation on miR-155/Nrf2 axis, which suppressed oxidative stress-induced pyroptosis to improve trophoblast function and M2 macrophage polarization. LINC00240 could be a potential therapeutic target for preeclampsia.

Wild emmer introgression alters root-to-shoot growth dynamics in durum wheat in response to water stress.

Water deficit during the early vegetative growth stages of wheat (Triticum) can limit shoot growth and ultimately impact grain productivity. Introducing diversity in wheat cultivars to enhance the range of phenotypic responses to water limitations during vegetative growth can provide potential avenues for mitigating subsequent yield losses. We tested this hypothesis in an elite durum wheat background by introducing a series of introgressions from a wild emmer (Triticum turgidum ssp. dicoccoides) wheat. Wild emmer populations harbor rich phenotypic diversity for drought-adaptive traits. To determine the effect of these introgressions on vegetative growth under water-limited conditions, we used image-based phenotyping to catalog divergent growth responses to water stress ranging from high plasticity to high stability. One of the introgression lines exhibited a significant shift in root-to-shoot ratio in response to water stress. We characterized this shift by combining genetic analysis and root transcriptome profiling to identify candidate genes (including a root-specific kinase) that may be linked to the root-to-shoot carbon reallocation under water stress. Our results highlight the potential of introducing functional diversity into elite durum wheat for enhancing the range of water stress adaptation.

Impact of right ventricular impairment on morbidity and mortality in takotsubo syndrome-a meta-analysis of observational trials.

The impact of right ventricular impairment (RVI) on the morbidity and mortality of patients with Takotsubo syndrome (TTS) is well-debated. We conducted a meta-analysis to evaluate the mortality and morbidity risk associated with RVI compared with those without RVI in patients with TTS. A comprehensive search was performed in PubMed and Embase from inception to April 19, 2019. Our primary outcome of interest was in-hospital and long-term mortality. Other outcomes of interest were acute heart failure, left ventricular systolic function, tricuspid and mitral regurgitation, and length of hospital stay (LOS). We are reporting our outcomes as a cumulative odds ratio (OR). After an initial search, 10 studies with 1210 subjects were included in the quantitative analysis. Mean follow-up was 31 months. The odds of in-hospital and long-term mortality in TTS patients with and without RVI were not significantly different (p = 0.13 and 0.40). In TTS patients without RVI, the odds of acute heart failure, and mitral and tricuspid regurgitation were significantly lower at an OR of 0.26 (p < 0.0001), 0.40 (p = 0.0001), and 0.52 (p = 0.02) respectively. TTS patients with RVI had significantly lower mean LVEF (34% vs 41%, p = 0.03) and numerically higher mean LOS (9.5 days vs 7.6 days, p = 0.52) compared with those without RVI. The presence of RVI represents a severe form of TTS disease spectrum, characterized by severely reduced LVEF, higher incidence of MR and presence of TR. Although there was a trend toward increased in-hospital and long-term mortality, RVI in TTS does not portend worse survival.

Activation of GCN2 in macrophages promotes white adipose tissue browning and lipolysis under leucine deprivation.

We have previously shown that leucine deprivation stimulates browning and lipolysis in white adipose tissue (WAT), which helps to treat obesity. Adipose tissue macrophages (ATMs) significantly influence WAT browning and lipolysis. However, it is unclear whether ATMs are involved in leucine deprivation-induced browning and lipolysis in WAT; the associated signals remain to be elucidated. Here, we investigated the role of ATMs and the possible mechanisms involved in WAT browning and lipolysis under leucine-deprivation conditions. In this study, macrophages were depleted in mice by injecting clodronate-liposomes (CLOD) into subcutaneous white adipose tissues. Then, mice lacking general control nonderepressible 2 kinase (GCN2), which is a sensor of amino acid starvation, specifically in Lyz2-expressing cells, were generated to investigate the changes in leucine deprivation-induced WAT browning and lipolysis. We found leucine deprivation decreased the accumulation and changed the polarization of ATMs. Ablation of macrophages by CLOD impaired WAT browning and lipolysis under leucine-deprivation conditions. Mechanistically, leucine deprivation activated GCN2 signals in macrophages. Myeloid-specific abrogation of GCN2 in mice blocked leucine deprivation-induced browning and lipolysis in WAT. Further analyses revealed that GCN2 activation in macrophages reduced the expression of monoamine oxidase A (MAOA), resulting in increased norepinephrine (NE) secretion from macrophages to adipocytes, and this resulted in enhanced WAT browning and lipolysis. Moreover, the injection of CL316,243, a ß3-adrenergic receptor agonist, and inhibition of MAOA effectively increased the level of NE, leading to the enhancement of browning and lipolysis of WAT in myeloid GCN2 knockout mice under leucine deprivation. Collectively, our results demonstrate a novel function of GCN2 signals in macrophages, that is, regulating WAT browning and lipolysis under leucine deprivation. Our study provides important hints for possible treatment for obesity.

Association of maternal obesity with preterm birth phenotype and mediation effects of gestational diabetes mellitus and preeclampsia: a prospective cohort study.

BACKGROUND: The association between maternal obesity and preterm birth remains controversial and inconclusive, and the effects of gestational diabetes mellitus (GDM) and preeclampsia (PE) on the relationship between obesity and preterm birth have not been studied. We aimed to clarify the relationship between prepregnancy body mass index (BMI) and the phenotypes of preterm birth and evaluate the mediation effects of GDM and PE on the relationship between prepregnancy BMI and preterm birth. METHODS: We conducted a prospective cohort study of 43,056 women with live singleton births from 2017 through 2019. According to the WHO International Classification, BMI was classified as underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5-25 kg/m2), overweight (BMI 25-30 kg/m2) and obese (BMI ≥30 kg/m2). Preterm birth was defined as gestational age less than 37 weeks (extremely, < 28 weeks; very, 28-31 weeks; and moderately, 32-36 weeks). The clinical phenotypes of preterm birth included spontaneous preterm birth (spontaneous preterm labor and premature rupture of the membranes) and medically indicated preterm birth. We further analyzed preterm births with GDM or PE. Multivariable logistic regression analysis and causal mediation analysis were performed. RESULTS: Risks of extremely, very, and moderately preterm birth increased with BMI, and the highest risk was observed for obese women with extremely preterm birth (OR 3.43, 95% CI 1.07-10.97). Maternal obesity was significantly associated with spontaneous preterm labor (OR 1.98; 95% CI 1.13-3.47), premature rupture of the membranes (OR 2.04; 95% CI 1.08-3.86) and medically indicated preterm birth (OR 2.05; 95% CI 1.25-3.37). GDM and PE mediated 13.41 and 36.66% of the effect of obesity on preterm birth, respectively. GDM mediated 32.80% of the effect of obesity on spontaneous preterm labor and PE mediated 64.31% of the effect of obesity on medically indicated preterm birth. CONCLUSIONS: Maternal prepregnancy obesity was associated with all phenotypes of preterm birth, and the highest risks were extremely preterm birth and medically indicated preterm birth. GDM and PE partially mediated the association between obesity and preterm birth.